The present invention is directed toward bivalent ligands effective for blocking or inhibiting acyl-CoA; cholesterol O-acyltransferase enzyme (hereinafter, ACAT) which is a major regulator of cholesterol metabolism in cells. The blocking or inhibition of ACAT is useful in the prevention or treatment of a variety of physiological conditions associated with arterial vessels. In addition to the inhibition of ACAT the compounds have also been discovered to be effective in the lowering of plasma triglyceride levels and as a high-density lipoprotein (HDL) cholesterol elevator.
ACAT is found in most tissues including arterial, liver, adrenal gland, mammary gland, ovaries and intestine where it readily converts cholesterol into esterified cholesterol. Bell, F. P., Arterial Cholesterol Esterification By AcylCoAcholesterol Acyltransferase: Significance in Atherogenesis and its Inhibition by Drugs, Pharmacological Control of Hyperlipidaemia, JR Prous Sci. Pub., pp 409-422 (1986). Generally this reaction is in equilibrium with a hydrolysis reaction which converts the esterified cholesterol into cholesterol. The amount of available cholesterol which effects the balance of this equilibrium is dependent on many physiological factors and diet. Unforntunately, esterified cholesterol does not migrate through tissue as easily as cholesterol and can build-up and form obstructions. The accumulation of esterified cholesterol is one of the characteristic features of atheroschlerotic plaque. Therefore it would be of great advantage if the ACAT enzyme could be blocked or inhibited from turning cholesterol into esterified cholesterol in arterial tissues. Thus the compounds would be particularly useful in the treatment of the constriction or obstruction of arteries and atheroschlerosis.
These compounds, which are useful as ACAT inhibitors, also have the unprecedented effect of lowering plasma triglycerids and elevating HDL cholesterol. The potent hypotriglyceride effect of these compounds indicates that they would be useful in treating a variety of disorders associated with elevated triglyceride such as hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, hypercholesterolemia, chylomicronemia, and related disorders such as pancreatitis.
Triglyceride lowering is recognized as a desirable therapeutic goal given that elevated triglyceride levels are positively associated with pancreatitis and coronary artery disease in humans and are commonly seen in Type IV and Type V hyperlipoproteinemic patients and are associated with obesity, diabetes, .beta.-blocker therapy and chronic renal failure. The elevation of HDL cholesterol is also recognized as a desirable therapeutic goal in treating and preventing coronary artery diseases.